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Molecular and Cellular Biology, October 2000, p. 7751-7763, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

RB-Dependent S-Phase Response to DNA Damage

Karen E. Knudsen,1 Dana Booth,2,3 Soheil Naderi,2,3 Zvjezdana Sever-Chroneos,1 Anne F. Fribourg,1 Irina C. Hunton,2,3 James R. Feramisco,3,4 Jean Y. J. Wang,2,3 and Erik S. Knudsen1,*

Department of Cell Biology, University of Cincinnati, Cincinnati, Ohio 45267-0521,1 and Department of Biology,2 Cancer Center,3 and School of Medicine,4 University of California, San Diego, La Jolla, California 92093

Received 22 February 2000/Returned for modification 21 April 2000/Accepted 10 July 2000

The retinoblastoma tumor suppressor protein (RB) is a potent inhibitor of cell proliferation. RB is expressed throughout the cell cycle, but its antiproliferative activity is neutralized by phosphorylation during the G1/S transition. RB plays an essential role in the G1 arrest induced by a variety of growth inhibitory signals. In this report, RB is shown to also be required for an intra-S-phase response to DNA damage. Treatment with cisplatin, etoposide, or mitomycin C inhibited S-phase progression in Rb+/+ but not in Rb-/- mouse embryo fibroblasts. Dephosphorylation of RB in S-phase cells temporally preceded the inhibition of DNA synthesis. This S-phase dephosphorylation of RB and subsequent inhibition of DNA replication was observed in p21Cip1-deficient cells. The induction of the RB-dependent intra-S-phase arrest persisted for days and correlated with a protection against DNA damage-induced cell death. These results demonstrate that RB plays a protective role in response to genotoxic stress by inhibiting cell cycle progression in G1 and in S phase.

* Corresponding author. Mailing address: Department of Cell Biology, University of Cincinnati, Cincinnati, OH 45267-0521. Phone: (513) 558-8885. Fax: (513) 558-4454. E-mail: Erik.Knudsen{at}UC.edu.

Molecular and Cellular Biology, October 2000, p. 7751-7763, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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